CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) relapse is considered to be related to escape from antitumor immunity. Changes in the expression of immune checkpoints, including B7 homolog (H)1 and B7-H2, have been reported to contribute to AML progression. Binding of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) among other immune checkpoints on natural killer (NK) and T cells to CD155/CD112 in tumors is supposed to be inhibitory; however, the mechanism by which changes in CD155 and CD112 expression affect tumor immunity remains unclear. When the increased expression of CD155 and CD112 activates Raf-MEK-ERK pathway and Raf-MEK-ERK pathway is one of the targets of FMS-like tyrosine kinase 3 ( FLT3 ) inhibition. The present study investigated the alterations in CD155 and CD112 expression under FLT3 inhibition (quizartinib and gilteritinib) and studied its effect on NK and T cell cytotoxicity. CD155 and CD112 expression was analyzed using flow cytometry and reverse transcription-quantitative PCR in AML cell lines with or without FLT3 mutation using FLT3 inhibitors. CD155 and CD112 expression was specifically downregulated by FLT3 inhibition in FLT3 -mutated cell lines. Direct cytotoxicity and antibody-dependent cellular cytotoxicity against these cells by NK cells were enhanced. However, the cytotoxicity of γδ T cells with low TIGIT expression compared with NK cells was not enhanced in direct cytotoxicity assay using luciferase luminescence. The analysis of clinical trials from The Cancer Genome Atlas (TCGA) revealed that high CD155 and CD112 expression is associated with poor overall survival. The enhanced cytotoxicity of NK cells against CD155- and CD112-downregulated cells following FLT3 inhibition indicated CD155 and CD112 as possible targets of immunotherapy for AML using FLT3 inhibitors.

Research Progress of B-Cell Lymphoma/Leukemia-2 Inhibitor Combined with Azacytidine in the Targeted Therapy of Acute Myeloid Leukemia

“…Of the 31 patients treated, the cell smear method was used to detect bone marrow cell morphology, flow cytology to detect immunophenotyping, cell culture to detect cytogenetics, and second-generation sequencing to detect molecules. PCR fusion genes are detected by the method: Patient-Based 2016 WHO-AML/WHO-MDS Diagnostic Criteria Guidelines [ 9 ]. The prognosis grouping is based on the revision of the International Prognosis Scoring System (IPSS-R).…”

“…Based on disease typing analysis, MDS-EB-1 was 4 cases, ORR was 75.0% (3/4), CR was 1 case, mCR was 2 cases, and accompaniment was HI1. In one case, the median survival time was 11.5 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) months for 1 case with disease stabilization, the MDS-EB-2 was 8 cases, the ORR was 62.5% (5/8), and the mCR was 5. In 3 cases, the disease was stable, and the median survival time was 6.5 (3 to 19) months.…”

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

“…A functional threshold that controls the activatory or inhibitory NK cell function of this receptor has been proposed to explain this discrepancy. Meanwhile, TIGIT recognizes poliovirus receptor (PVR or CD155), Nectin-2 (CD112), or Nectin-3 overexpressed in hematologic cancers ( 203 , 204 ). The blockade of TIM-3 or TIGIT in preclinical studies improves NK cell cytotoxic potency against solid and hematologic malignancies ( 205 – 209 ) and currently neutralizing antibodies are being tested in several clinical trials (e.g.…”

Role of Biomarkers in FLT3 AML

“…Such biomarkers are useful for clinical practice and therapeutic development [ 14 ]. Various molecular markers, such as phosphorylation, and immune markers have been used in various studies [ 17 , 18 ].…”

“…Another study identified that the expression of immune checkpoint markers CD155 and CD112 (using flow cytometry and real-time PCR) was specifically downregulated upon treatment with gilteritinib and quizartinib in FLT3-mutated cell models. Thus, CD155 and CD112 have the potential to serve as PD biomarkers for FLT3-ITD AML patients [ 17 ].…”